Lupus Nephritis (LN)
Lupus nephritis (LN), characterized by inflammation of the kidney, is a complication which occurs in a subpopulation of patients with Systemic Lupus Erythematosus (SLE) and is one of the most serious complications caused by SLE. (MedlinePlus)
SLE is a debilitating autoimmune disease of great clinical diversity and can manifest itself in different ways and lead to a number of complications, e.g., arthritis, arthralgia, and myalgia, depending on the patient and the parts of the body affected. The precise etiology of SLE has not yet been determined, but hormonal, genetic, viral and environmental factors may precipitate the disease. SLE prevalence varies across ethnicities and geographic regions with an occurrence rate of 15 to 50 cases per 100,000 persons. SLE is most common in women of childbearing age (15-44) with a female-to-male ratio varying from 4.3 to 13.6 (Petri, 2002). Virtually all body systems may be involved, including the musculoskeletal, mucocutaneous, cardiovascular, neurological, respiratory, renal, ophthalmic hematological and gastrointestinal systems.
Due to the great clinical diversity and idiopathic nature of SLE, management of idiopathic SLE depends on its specific manifestations and severity. (The Merck Manual, 1999) Therefore, medications suggested to treat SLE generally are not necessarily effective for the treatment of all manifestations of and complications resulting from SLE, e.g., LN.
LN usually arises early in the disease course, within 5 years of diagnosis. The pathogenesis of LN is believed to derive from deposition of immune complexes in the kidney glomeruli that initiates an inflammatory response (Brent, 2008).
An estimated 30-50% of patients with SLE develop nephritis that requires medical evaluation and treatment. LN is a progressive disease, running a course of clinical exacerbations and remissions. Early detection and treatment can significantly improve renal outcome and prognosis. Although over the last decades, treatment of LN has been greatly improved, 5 and 10-year survival rates are documented as 85% and 73%, respectively (Brent, 2008). LN morbidity is related to the renal disease itself, as well as to treatment-related complications.
Renal biopsy is considered for any patient with SLE who has clinical or laboratory evidence of active nephritis, in order to determine the histological type as well as the appropriate treatment management and prognosis. (Bevra, 2001; Brent, 2008)
The histological classification of LN was revised by the International Society of Pathology/Renal Pathology Society (ISN/RPS) in 2003 and is based on light microscopy, immunofluorescence, and electron microscopy findings from renal biopsy specimens (Foster, 2004). These classifications describes 6 major classes of LN: Class I and II—mesangial LN, Class III and IV—proliferative LN, class V—membranous LN and class VI—advanced sclerosis LN. The ISN/RPS classifications were based on earlier classifications by the World Health Organization (WHO) published in 1974 and 1982.
There is no definitive treatment or cure for LN. The principal goals of therapy is to normalize renal function, urine sediment and proteinuria, reduce the frequency of relapses or prevent the progressive loss of renal function through mild, moderate and severe renal impairment to end stage renal disease (ESRD) requiring dialysis or kidney transplantation. Therapy varies pending on the histopathological findings as well as the clinical manifestations.
Corticosteroids and cytotoxic or immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil (MMF) are the standard of care for patients with aggressive proliferative LN, while less aggressive treatment options may be considered for purely membranous LN or mesangial LN. Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin II Receptor Blockers (ARBs) may control blood pressure and reduce proteinuria.
Most of the above mentioned treatments are not specifically indicated for the treatment of SLE/LN and treatment protocols vary.
Treatment of accompanying SLE signs, symptoms, and complications may additionally include a combination of NSAIDs, antimalarial agents, antihypertensives, calcium supplements or bisphosphonate, anti-coagulants and others.
While many patients fail to respond or respond only partially to the standard of care medications listed above, the long-term use of high doses of corticosteroids and cytotoxic therapies may have profound side effects such as bone marrow depression, increased infections with opportunistic organisms, irreversible ovarian failure, alopecia and increased risk of malignancy. Infectious complications coincident with active SLE and its treatment with immunosuppressive medications are the most common cause of death in patients with SLE.
There is, therefore, a need for alternative therapies with better risk-benefit profiles for the treatment of lupus nephritis.
Laquinimod is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005). Laquinimod and its sodium salt form are described, for example, in U.S. Pat. No. 6,077,851. The effects of laquinimod on lupus nephritis have not been reported.
Mycophenolate Mofetil (MMF)
Mycophenolate mofetil (MMF), sold under the brand name CellCept®, is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent, and inosine monophosphate dehydrogenases (IMPDH) inhibitor. The chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isogenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C23H31NO7 and a molecular weight of 433.50. CellCept® is indicated for prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants (Physician's Desk Reference, 2009).
CellCept® is available for oral administration as capsules containing 250 mg of mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a powder for oral suspension, which when constituted contains 200 mg/mL mycophenolate mofetil. CellCept® is also available for Intravenous administration as a sterile white to off-white lyophilized powders in vials containing mycophenolate mofetil hydrochloride. Each vial of IV contains the equivalent of 500 gm MMF as the hydrochloride salt. The recommended dose for CellCept® is 1 g administered orally or via IV (over no less than 2 hours) twice daily (daily dose of 2 g) for use in renal transplant patients. The recommended dose of CellCept® oral suspension is 600 mg/m2 administered twice daily up to a maximum daily dose of 2 g/1-mL oral suspension (Physician's Desk Reference, 2009).
Combination Therapy
The administration of two drugs to treat a given condition, such as a form of lupus, raises a number of potential problems. In vivo interactions between two drugs are complex. The effects of any single drug are related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other and hence, alter the effects of the other. For instance, one drug may inhibit, activate or induce the production of enzymes involved in a metabolic route of elimination of the other drug (Guidance for Industry, 1999). Thus, when two drugs are administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with, the therapeutic activity of the other in a human subject.
Not only may the interaction between two drugs affect the intended therapeutic activity of each drug, but the interaction may increase the levels of toxic metabolites (Guidance for Industry, 1999). The interaction may also heighten or lessen the side effects of each drug. Hence, upon administration of two drugs to treat a disease, it is unpredictable what change will occur in the negative side profile of each drug.
Additionally, it is difficult to accurately predict when the effects of the interaction between the two drugs will become manifest. For example, metabolic interactions between drugs may become apparent upon the initial administration of the second drug, after the two have reached a steady-state concentration or upon discontinuation of one of the drugs (Guidance for Industry, 1999).